Tumor-Specific Targeting of Folate-Derivatized Drugs

叶酸衍生药物的肿瘤特异性靶向

• 批准号: 6455374
• 负责人: PHILIP Stewart LOW
• 金额: $ 24.94万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6455374
• 关键词: autoradiography; chemical conjugate; clinical research; cytotoxicity; drug delivery systems; drug design /synthesis /production; fluoresceins; fluorescence microscopy; folate; human subject; immunotherapy; laboratory mouse; molecular size; neoplasm /cancer chemotherapy; paclitaxel; receptor binding; receptor expression; transport proteins

DESCRIPTION (provided by applicant): The receptor for folic acid is an established tumor marker, showing elevated expression in many epithelial cancers, including cancers of the ovary, cervix, endometrium, kidney, brain and head and neck. When folic acid is covalently linked to another molecule or particle, it may still bind with high affinity (KD -1 0-9M) to the folate receptor (FR), but will lose all affinity for the reduced folate carrier (a transport protein that mediates folate uptake by many nonmalignant cells). Folate conjugates are, therefore, bound and internalized only by FR-expressing cells. Because of FR upregulation on cancer cells, folate ligation has been hypothesized to convert the vitamin into a molecular "Trojan Horse" that can facilitate targeting and delivery of attached therapeutic or imaging agents into malignant cells. While results from cell culture studies have been very encouraging, few quantitative data are available to permit an assessment of the therapeutic potential of folatemediated drug targeting in human patients. In our first two aims, we propose to first obtain this quantitative information. In the last two aims, we will test the therapeutic potential of the strategy in mouse tumor models. First, we will measure the in vivo recycling rate of FR in several relevant cancer models. Together with published data on the levels of FR expression in various human cancers, this recycling information should enable a more quantitative estimate of the total uptake and delivery capacity of the folate-mediated targeting pathway. Second, we will address how the size of a folate conjugate impacts its accessibility to cancer cells in vivo. Recent data indicate that the ability of folate conjugates to bind to and decorate cells throughout a tumor mass may be limited by molecular size. Quantitative data on this matter will be required to guide the design of folate-linked therapeutics. Third, we will synthesize and test folate-conjugated cytotoxic drugs for therapeutic efficacy in vivo. And finally, we will define the molecular and cellular bases of a novel folate-targeted immunotherapy that we have already shown can eradicate established tumors in mice without damaging normal tissues.

描述（由申请人提供）：叶酸的受体是 已建立的肿瘤标记，显示许多上皮的表达升高 癌症，包括卵巢，子宫颈，子宫内膜，肾脏，大脑和大脑的癌症 头和脖子。当将叶酸共价链接到另一个分子或 粒子，它仍然可以与叶酸高亲和力（KD -1 0-9m）结合 受体（FR），但会失去对减少叶酸载体的所有亲和力（a 转运蛋白介导了许多非恶性细胞的叶酸摄取）。 因此，叶酸结合物仅通过表达构造和内在化 细胞。由于癌细胞上的FR上调，叶酸结扎一直是 假设可以将维生素转化为分子“特洛伊木马” 促进与附着的治疗或成像剂的靶向和交付 进入恶性细胞。虽然细胞培养研究的结果非常 令人鼓舞的是，很少有定量数据可以评估 人类患者中叶状性药物靶向的治疗潜力。在 我们的前两个目标，我们建议首先获得此定量信息。 在最后两个目标中，我们将测试该战略的治疗潜力 小鼠肿瘤模型。首先，我们将测量FR的体内回收率 几种相关的癌症模型。以及已发布的有关水平的数据 在各种人类癌症中的FR表达，这些回收信息应 对总吸收能力和交付能力进行更定量的估计 叶酸介导的靶向途径。其次，我们将解决尺寸 叶酸结合物影响其对体内癌细胞的可及性。最近的 数据表明，叶酸结合物结合并装饰的能力 整个肿瘤质量的细胞可能受到分子大小的限制。定量 需要有关此问题的数据来指导叶酸连接的设计 疗法。第三，我们将合成并测试叶酸结合的细胞毒性 体内治疗功效的药物。最后，我们将定义 我们的分子和细胞碱基的新型叶酸靶向免疫疗法 已经显示出来可以根除小鼠中已建立的肿瘤而不会损害 正常组织。